Recepteur d'Origine Nantais (RON), also known as Macrophage Stimulating Protein Receptor (MSP R, or MST1-R), is a member of the MET family of receptor tyrosine kinases that binds the ligand known as Macrophage Stimulating Protein (MSP). RON is composed of a 40 kDa extracellular a chain and a 150 kDa transmembrane β chain. The β chain is responsible for the intrinsic kinase activity, and the extracellular portions of the two chains function together as the ligand binding domain (Wagh et al., 2008, ADV. CANCER RES. 100:1-33).
MSP binding to RON activates multiple downstream signaling pathways and mediates multiple cellular activities. RON pathway dysregulation is involved in inflammatory response, wound healing and liver regeneration. RON signaling can sustain tumor growth, survival, motility, invasion and angiogenesis in certain malignancies. The RON protein exists in several splice variants, some of which are tumorigenic in animal models of cancer. One such splice variant is delta 160 RON, which lacks exons 5 and 6 (Lu et al., 2007, CANCER LETT. 257:157-164).
When activated by ligand binding, RON activates the PI3K/AKT pathway and the MAPK pathway. RON also affects cells through interactions with other receptors, e.g., c-Met, integrins and EGFR. To date, no activating mutations in RON exons have been reported. Alternative splicing and overexpression appear to be the main mechanisms for constitutive activation of the receptor. Several small molecule inhibitors have been reported that inhibit multiple receptor tyrosine kinases, including RON, examples of which include EXCEL-2880, (Qian et al., 2009, CANCER RES. 69:8009-8016) and BMS-77607 (Schroeder et al., 2009 J. MED CHEM. 52:1251-1254). A dual c-met/RON inhibitor has also been reported, Amgen compound I (Zhang et al., 2008, CANCER RES. 68:6680-6687). A recent publication describes a selective RON small molecule inhibitor (Raeppel et al., 2010 BIOORG MED CHEM LETT 20:2745-9). Several antibodies that inhibit human RON activity have been reported (Huet et al., US 2009/0226442; Pereira et al., US 2009/0136510; Zhu et al., WO 2006/020258; Pereira et al., WO 2005/120557; and commercial antibody MAB691, R&D Systems, Minneapolis, Minn.).
Naturally occurring antibodies are multimeric proteins that contain four polypeptide chains (FIG. 1). Two of the polypeptide chains are called heavy chains (H chains), and two of the polypeptide chains are called light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL in FIG. 1) and one constant region (CL in FIG. 1). The heavy chain consists of one variable region (VH in FIG. 1) and at least three constant regions (CH1, CH2 and CH3 in FIG. 1). The variable regions determine the specificity of the antibody. Each variable region comprises three hypervariable regions also known as complementarity determining regions (CDRs) flanked by four relatively conserved framework regions (FRs). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies.
Although antibodies that bind RON are known in the art, there is still a need for improved RON antibodies that can be used as therapeutic agents.